Molecular Mechanisms of Medicinal Plant Securinega suffruticosa-derived Compound Securinine against Spinal Muscular Atrophy based on Network Pharmacology and Experimental Verification

Title:Molecular Mechanisms of Medicinal Plant Securinega suffruticosa-derived Compound Securinine against Spinal Muscular Atrophy based on Network Pharmacology and Experimental Verification

Volume: 30 Issue: 15

Author(s): Yinhong Zhang, Jing He, Lifeng Xiang, Xinhua Tang, Shiyu Wang, Aoyu Li, Chaoyan Wang, Li Li*Baosheng Zhu*

Affiliation:

• The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
• School of Medical, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
• Department of Pediatrics, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan, China

• NHC Key Laboratory of Preconception Health Birth in Western China, Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, Department of Medical Genetics, Yunnan Provincial Clinical Research Center for Birth Defects and Rare Diseases, The First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan, China
• The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
• School of Medical, Kunming University of Science and Technology, Kunming 650500, Yunnan, China

Keywords: Experimental verification, network pharmacology, securinine, spinal muscular atrophy, survival motor neuron, gene regulation.

Abstract:

Background: Spinal Muscular Atrophy (SMA) is a severe motor neuronal disorder with high morbidity and mortality. Securinine has shown the potential to treat SMA; however, its anti-SMA role remains unclear.

Objective: This study aims to reveal the anti-SMA mechanisms of securinine.

Methods: Securinine-associated targets were acquired from Herbal Ingredients' Targets (HIT), Similarity Ensemble Approach (SEA), and SuperPred. SMA-associated targets were obtained from GeneCards and Dis- GeNET. Protein-protein Interaction (PPI) network was constructed using GeneMANIA, and hug targets were screened using cytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfifiler. Molecular docking was conducted using Pymol and Auto- Dock. In vitro assays were used to verify the anti-SMA effects of securinine.

Results: Twenty-six intersection targets of securinine and SMA were obtained. HDAC1, HDAC2, TOP2A, PIK3R1, PRMT5, JAK2, HSP90AB1, TERT, PTGS2, and PAX8 were the core targets in PPI network. GO analysis demonstrated that the intersecting targets were implicated in the regulation of proteins, steroid hormones, histone deacetylases, and DNA transcription. KEGG analysis, pathway-pathway, and hub target-pathway networks revealed that securinine might treat SMA through TNF, JAK-STAT, Ras, and PI3K-Akt pathways. Securinine had a favorable binding affinity with HDAC1, HSP90AB, JAK2, PRMT5, PTGS2, and TERT. Securinine rescued viability suppression, mitochondria damage, and SMN loss in the SMA cell model. Furthermore, securinine increased HDAC1 and PRMT5 expression, decreased PTGS2 expression, suppressed the JAK2-STAT3 pathway, and promoted the PI3K-Akt pathway.

Conclusion: Securinine might alleviate SMA by elevating HDAC1 and PRMT5 expression and reducing PTGS2 via JAK2-STAT3 suppression and PI3K-Akt activation.

Cite this article as:

Zhang Yinhong, He Jing, Xiang Lifeng, Tang Xinhua, Wang Shiyu, Li Aoyu, Wang Chaoyan, Li Li*, Zhu Baosheng*, Molecular Mechanisms of Medicinal Plant Securinega suffruticosa-derived Compound Securinine against Spinal Muscular Atrophy based on Network Pharmacology and Experimental Verification, Current Pharmaceutical Design 2024; 30 (15) . https://dx.doi.org/10.2174/0113816128288504240321041408